Indol-3-yl-carbonyl-azaspiro derivatives

ABSTRACT

This invention relates to indol-3-yl-carbonyl-azaspiro derivatives which act as V1a receptor antagonists and which are represented by Formula I:  
                 
 
wherein the azaspiro-head group A and the residues R 1 , R 2  and R 3  are as defined herein. The invention further relates to pharmaceutical compositions containing such compounds, their use for treating dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders, and methods of preparation thereof.

Priority to Related Applications

This application claims the-benefit of European Application No.05108966.2, filed Sep. 28, 2005, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Vasopressin is a 9 amino acid peptide mainly produced by theparaventricular nucleus of the hypothalamus. Three vasopressinreceptors, all belonging to the class I G-protein coupled receptors, areknown. The V1a receptor is expressed in the brain, liver, vascularsmooth muscle, lung, uterus and testis, the V1b or V3 receptor isexpressed in the brain and pituitary gland, the V2 receptor is expressedin the kidney where it regulates water excretion and mediates theantidiuretic effects of vasopressin.

In the periphery vasopressin acts as a neurohormone and stimulatesvasoconstriction, glycogenolysis and antidiuresis. In the brainvasopressin acts as a neuromodulator and is elevated in the amygdaladuring stress (Ebner, K., C. T. Wotjak, et al. (2002). “Forced swimmingtriggers vasopressin release within the amygdala to modulatestress-copping strategies in rats.” Eur J Neurosci 15(2): 384-8). TheV1a receptor is extensively expressed in the brain and particularly inlimbic areas like the amygdala, lateral septum and hippocampus which areplaying an important role in the regulation of anxiety. Indeed V1aknock-out mouse show a reduction in anxious behavior in the plus-maze,open field and light-dark box (Bielsky, I. F., S. B. Hu, et al. (2003).“Profound Impairment in Social Recognition and Reduction in Anxiety-LikeBehavior in Vasopressin V1a Receptor Knockout Mice.”Neuropsychopharmacology). The downregulation of the V1a receptor usingantisense oligonucleotide injection in the septum also causes areduction in anxious behavior (Landgraf, R., R. Gerstberger, et al.(1995). “V1 vasopressin receptor antisense oligodeoxynucleotide intoseptum reduces vasopressin binding, social discrimination abilities, andanxiety-related behavior in rats.” Regul Pept 59(2): 229-39).

The V1a receptor is also mediating the cardiovascular effects ofvasopressin in the brain by centrally regulating blood pressure andheart rate in the solitary tract nucleus (Michelini, L. C. and M. Morris(1999). “Endogenous vasopressin modulates the cardiovascular responsesto exercise.” Ann N Y Acad Sci 897: 198-211). In the periphery itinduces the contraction of vascular smooth muscles and chronicinhibition of the V1a receptor improves hemodynamic parameters inmyocardial infarcted rats (Van Kerckhoven, R., I. Lankhuizen, et al.(2002). “Chronic vasopressin V(1A) but not V(2) receptor antagonismprevents heart failure in chronically infarcted rats.” Eur J Pharmacol449(1-2): 135-41).

Thus vasopressin receptor antagonists are useful as therapeutics in theconditions of dysmenorrhea, hypertension, chronic heart failure,inappropriate secretion of vasopressin, liver cirrhosis, nephroticsyndrome, obsessive compulsive disorder, anxiety and depressivedisorders.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I):

whereinR¹ is

H,

C₁₋₆-alkyl,

aryl, 5 or 6 membered heteroaryl or sulfonylaryl, each of which isoptionally substituted by one or more B,

—(CH₂)_(m)—R^(a) wherein R^(a) is:

-   -   CN,    -   OR^(i),    -   NR^(i)RU^(ii), or    -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or        6 membered heteroaryl, each of which is optionally substituted        by one or more B,

or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:

-   -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   C₃₋₆-cycloalkyl,    -   —(CH₂)_(m)—NR^(iii)R^(iv),    -   NR^(i)R^(ii), or    -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or        6 membered heteroaryl, each of which is optionally substituted        by one or more B,        or R¹ and R³ together with the indole ring to which they are        attached form a 5 or 6 membered heterocycloalkyl which is        optionally substituted by ═O;        there is one or more R², wherein each R² is the same or        different,        R² is one or more H,

OH,

halo,

CN,

nitro,

C₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv),

C₁₋₆-alkoxy,

—O—CH₂—C₂₋₆-alkenyl, or

benzyloxy,

or two R² together with the indole ring to which they are attached-forman oxo or dioxo bridge;

R³ is H,

halo,

—(CO)—R^(c), wherein R^(c) is:

-   -   C₁₋₆-alkyl,    -   —(CH₂)_(n)—NR^(i)R^(ii),    -   —(CH₂)n—NR^(iii)R^(iv),    -   5 or 6 membered heterocycloalkyl optionally substituted by        C₁₋₆-alkyl, or    -   C₁₋₆-alkyl or aryl, each of which is optionally substituted by        -   halo,        -   —O(CO)—C₁₋₆-alkyl, or        -   —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyl optionally            substituted by halo or nitro, or R^(d) is aryl or a 5 or 6            membered heteroaryl, each of which is optionally substituted            by halo, nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl;            B is halo,

CN,

NR^(i)R^(ii),

C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,

C₁₋₆-alkoxy,

C₁₋₆-haloalkoxy,

C₃₋₆-cycloalkyl,

—C(O)O—C₁₋₆-alkyl,

—C(O) NR^(i)R^(ii),

—C(O)—C₁₋₆-alkyl,

—S(O)₂—C₁₋₆-alkyl,

—S(O)₂—NR^(i)R^(ii), or (CR^(iii)R^(iv))_(n)-phenyl, or(CR^(iii)R^(iv))_(n)-5 or 6 membered heteroaryl wherein the phenyl or 5or 6 membered heteroaryl moiety-is optionally substituted by one or moresubstituent(s) selected from the group consisting of halo, CN,NR^(i)R^(ii), C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl,—C(O)—NR^(i)R^(ii), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and—S(O)₂—NR^(i)R^(ii);

R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂-C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv);

R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;

m is 1 to 6;

n is 0 to 4; and

A is either a group of the formula (a) or (b):

whereinR⁴ is is H or C₁₋₆-alkyl; andR⁵ is aryl optionally substituted by halo;or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can contain some asymmetric carbon atoms.Accordingly, the present invention includes all stereioisomeric forms ofthe compounds of formula (I), including each of the individualenantiomers and mixtures thereof.

The invention also-provides pharmaceutical compositions containing thecompounds of the invention and a pharmaceutically acceptable carrier aswell as processes for preparation of such compounds and compositions.

Compounds of formula (I) have good activity on the Via receptor.Therefore, the invention provides methods for the treatment ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders. Such methodscomprise administering a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

The preferred indications with regard to the present invention are thetreatment of anxiety and depressive disorders.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

As used herein, the term “aryl” means a monovalent cyclic aromatichydrocarbon moiety consisting of a mono-, bi- or tricyclic aromaticring. Examples of aryl moieties include, but are not limited to,optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl,indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl,aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, anddiphenylisopropylidenyl, as well as those specifically illustrated bythe examples herein below. Substituents for aryl include, but are notlimited to, halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy. Preferred aryl arephenyl and naphthyl, and still more preferably phenyl. The aryl moietiesof the invention further can be ortho substituted by two substituentswhich together with the carbons of the aryl moiety form a fused,saturated or partially saturated, 5- to 6-membered ring containing oneor two heteroatoms selected from O and N. Preferably the additional ringis a 5- to 6-membered ring containing two oxygen atoms. Examples of suchsubstituted aryl moieties include, but are not limited to,benzodioxanyl, dihydro-benzofuranyl, benzodioxolyl, benzopyranyl,benzoxazinyl, benzoxazinonyl, benzopiperidinyl, benzopiperazinyl,benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl,ethylenedioxyphenyl, as well as those specifically illustrated by theexamples herein below.

The term “C₁₋₆-alkyl” denotes a saturated straight- or branched-chainhydrocarbon group containing from 1 to 6 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl andthe like. Preferred C₁₋₆-alkyl groups are C₁₋₄-groups, i.e. with 1-4carbon atoms.

The term “C₁₋₆-alkoxy” denotes an alkyl group as defined above, attachedvia an oxygen atom. Preferred C₁₋₆-alkoxy groups are methoxy and ethoxyas well as those specifically illustrated by the examples herein below.

The term “C₂₋₆-alkenyl” denotes a carbon chain of 2 to 6 carbon atomscomprising at least one double bond in its chain. C₂₋₆-alkenyl-groupsinclude ethenyl, propen-1-yl, propen-2-yl, buten-1-yl, buten-3-yl,penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl, hexen-1-yl,hexen-2-yl, hexen-3-yl, hexen-4-yl and hexen-5-yl, as well as thosespecifically-illustrated by the examples herein below.

The term “benzyloxy” denotes a benzyl group attached via an oxygen atom.

The term “halogen” or “halo” denotes chlorine (Cl), iodine (I), fluorine(F) and bromine (Br).

The term “C₁₋₆-haloalkyl” denotes a C₁₋₆-alkyl group as defined abovewhich is substituted by one or more halogen atom. Examples ofC₁₋₆-haloalkyl include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexylsubstituted by one or more Cl, F, Br or I atom(s) as well as thosegroups specifically illustrated by the examples herein below. PreferredC₁₋₆-haloalkyl are difluoro- or trifluoro-methyl or ethyl.

“C₁₋₆-haloalkoxy” denotes a C₁₋₆-alkoxy group as defined above which issubstituted by one or more halogen atom. Examples of C₁₋₆-haloalkoxyinclude, but are not limited to, methoxy or ethoxy, substituted by oneor more Cl, F, Br or I atom(s) as well as those groups specificallyillustrated by the examples herein below. Preferred C₁₋₆-haloalkoxy aredifluoro- or trifluoro-methoxy or ethoxy.

The term “C₃₋₆-cycloalkyl” denotes a monovalent or divalent saturatedcarbocyclic moiety consisting of a monocyclic ring. Cycloalkyl canoptionally be substituted with one, two, three or four substituents,wherein each substituent is independently hydroxy, C₁₋₆-alkyl,C₁₋₆-alkoxy, halogen, amino, unless otherwise specifically indicated.Examples of cycloalkyl moieties include optionally substitutedcyclopropyl, optionally substituted cyclobutyl, optionally substitutedcyclopentyl and optionally substituted cyclohexyl as well as thosespecifically illustrated by the examples herein below.

The term “4 to 7 membered heterocycloalkyl” means a monovalent saturatedmoiety, consisting of one ring having 4 to 7 atoms as ring members,containing one, two, or three heteroatoms chosen from nitrogen, oxygenor sulfur, the rest of the ring atoms being carbon atoms 4 to 7 memberedheterocycloalkyl can optionally be substituted with one, two, three orfour substituents, wherein each, substituent is independently hydroxy,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-thioalkyl, halo, C₁₋₆-haloalkyl,C₁₋₆-hydroxyalkyl, alkoxycarbonyl, amino, C₁₋₆-alkylamino,di(C₁₋₆)alkylamino, aminocarbonyl, or carbonylamino, unless otherwisespecifically indicated. Examples of heterocyclic moieties include, butare not limited to, optionally substituted oxetane, optionallysubstituted tetrahydro-furanyl, optionally substituted piperidinyl,optionally substituted pyrrolidinyl, optionally substituted morpholinyl,optionally substituted piperazinyl, and the like or those which arespecifically exemplified herein. Substituents can be selected fromC₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl, halo, CN, OH, NH₂, as well asthose substituents which are specifically illustrated in the exampleshereinafter.

The term “5 or 6 membered heteroaryl” means an aromatic ring having 5 or6 ring atoms as ring members, containing one, two, or three ringheteroatoms selected from N, O, or S, the rest of the ring atoms beingcarbon atoms. 5 or 6 heteroaryl can optionally be substituted with one,two, three or four substituents, wherein each substituent isindependently hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-thioalkyl, halo,C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl, alkoxycarbonyl, amino,C₁₋₆-alkylamino, di(C₁₋₆)alkylamino, aminocarbonyl, or carbonylamino,unless otherwise specifically indicated. Examples of heteroaryl moietiesinclude, but are not limited to, optionally substituted imidazolyl,optionally substituted oxazolyl, optionally substituted thiazolyl,optionally substituted pyrazinyl, optionally substituted pyrrolyl,optionally substituted pyrazinyl, optionally substituted pyridinyl,optionally substituted pyrimidinyl, optionally substituted furanyl, andthose which are specifically exemplified herein.

The term “sulfonylaryl” denotes an aryl group as defined hereinabovewhich is attached via a sulfonyl group.

The expression “two R² together with the indole ring to which they areattached form an oxo or dioxo bridge” denotes an oxo or dioxo bridge ofthe following formulae:

which bind two adjacent carbon atoms of the phenyl or indole ring of thecompound of formula (I) to which either R² is binding.

Examples of groups illustrating the expression “R¹ and R³ together withthe indole ring to which they are attached form a 5 or 6 memberedheterocycloalkyl which is optionally substituted by ═O” are:

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid, as well as thosespecifically illustrated by the examples herein below.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The present invention provides compounds of formula (I):

whereinR¹ is

H,

C₁₋₆-alkyl,

aryl, 5 or 6 membered heteroaryl or sulfonylaryl, each of which isoptionally substituted by one or more B,

—(CH₂)_(m)—R^(a) wherein R^(a) is:

-   -   CN,    -   OR^(i),    -   NR^(i)R^(ii), or    -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or        6 membered heteroaryl, each of which is optionally substituted        by one or more B,

or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:

-   -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   C₃₋₆-cycloalkyl,    -   —(CH₂)_(m)—NR^(iii)R^(iv),    -   NR^(i)R^(ii), or

C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6membered heteroaryl, each of which is optionally substituted by one ormore B,

or R¹ and R³ together with the indole ring to which they are attachedform a 5 or 6 membered heterocycloalkyl which is optionally substitutedby ═O;

there is one or more R², wherein each R² is the same or different,

R² is one or more H,

OH,

halo,

CN,

nitro,

C₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv),

C₁₋₆-alkoxy,

—O—CH₂—C₂₋₆-alkenyl, or

benzyloxy,

or two R² together with the indole ring to which they are attached forman oxo or dioxo bridge;

R³ is H,

halo,

—(CO)—R^(c), wherein R^(c) is:

-   -   C₁₋₆-alkyl,    -   —(CH₂)_(n)—NR^(i)R^(ii),    -   —(CH₂)_(n)—NR^(iii)R^(iv), or    -   5 or 6 membered heterocycloalkyl optionally substituted by        C₁₋₆-alkyl, or    -   C₁₋₆-alkyl or aryl, each of which is optionally substituted by        -   halo,        -   —O(CO)—C₁₋₆-alkyl, or        -   —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyl optionally            substituted by halo or nitro, or R^(d) is aryl or a 5 or 6            membered heteroaryl, each of which is optionally substituted            by halo, nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl;            B is halo,

CN,

NR^(i)R^(ii),

C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,

C₁₋₆-alkoxy,

C₁₋₆-haloalkoxy,

C₃₋₆-cycloalkyl,

—C(O)O—C₁₋₆-alkyl,

—C(O) NR^(i)R^(ii),

—C(O)—C₁₋₆-alkyl,

—S(O)₂—C₁₋₆-alkyl,

—S(O)₂—NR^(i)R^(ii), or

(CR^(iii)R^(iv))_(n)-phenyl, or (CR^(iii)R^(iv))_(n)-5 or 6 memberedheteroaryl wherein the phenyl or 5 or 6 membered heteroaryl moiety isoptionally substituted by one or more substituent(s) selected from thegroup consisting of halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionallysubstituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and —S(O)₂—NR^(i)R^(ii);

R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv);

R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;

m is 1 to 6;

n is 0 to 4; and

A is either a group of the formula (a) or (b):

whereinR⁴ is is H or C₁₋₆-alkyl; andR⁵ is aryl optionally substituted by halo;or a pharmaceutically acceptable salt thereof.

In detail, the present invention relates to compounds of the generalformula (I):

whereinR¹ is H,

C₁₋₆-alkyl,

aryl, 5 or 6 membered heteroaryl or sulfonylaryl each of which isoptionally substituted by one-or more B,

—(CH₂)_(m)—R^(a) wherein R^(a) is:

-   -   CN,    -   OR¹,    -   NR^(i)R^(ii), or    -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or        6-membered heteroaryl, each of which is optionally        substituted-by one or more B,

or —(CH₂)_(n)—(CO)'R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:

C₁₋₆-alkyl,

-   -   C₁₋₆-alkoxy,    -   C₃₋₆-cycloalkyl,    -   —(CH₂)_(m)—NR^(iii)R^(iv),    -   NR^(i)R^(ii), or    -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl5 aryl, or 5 or        6 membered heteroaryl, each of which is optionally substituted        by one or more B,        or R¹ and R³ together with the indole ring to which they are        attached form a 5 or 6 membered heterocycloalkyl which is        optionally substituted by ═O;        there is one or more R₂, wherein each R² is the same or        different,        R² is one or more H,

OH,

halo,

CN,

nitro, or

C₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv), C₁₋₆-alkoxy,—O—CH₂—C₂₋₆-alkenyl, or benzyloxy,

or two R²-together with the indole ring to which they are attached forman oxo or dioxo bridge;

R³ is H,

halo,

or —(CO)—R^(c), wherein R^(c) is:

-   -   C₁₋₆-alkyl,    -   —(CH₂)_(n)—NR^(i)R^(ii),    -   (CH₂)_(n)—NR^(iii)R^(iv),    -   5 or 6 membered heterocycloalkyl optionally substituted by        C₁₋₆-alkyl, or    -   C₁₋₆-alkyl or aryl, each of which is optionally substituted by        halo, —O(CO)—C₁₋₆-alkyl, or —NH(CO)R^(d), wherein R^(d) is        C₁₋₆-alkyl optionally substituted by halo or nitro, or R^(d) is        aryl or a 5 or 6 membered heteroaryl, each of which is        optionally substituted by halo, nitro, C₁₋₆-alkyl or        C₁₋₆-haloalkyl;        B is halo,

CN,

NR^(i)R^(ii),

C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,

C₁₋₆-alkoxy,

C₁₋₆-haloalkoxy,

C₃₋₆-cycloalkyl,

—C(O)O—C₁₋₆-alkyl,

—C(O) NR^(i)R^(ii),

—C(O)—C₁₋₆-alkyl,

—S(O)₂—C₁₋₆-alkyl,

—S(O)₂—NR^(i)R^(ii), or

(CR^(iii)R^(iv))_(n)-phenyl, or (CR^(iii)R^(iv))_(n)-5 or 6 memberedheteroaryl wherein the phenyl or 5 or 6 membered heteroaryl moiety isoptionally substituted by one or more substituent(s) selected from thegroup consisting of halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionallysubstituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and —S(O)₂—NR^(i)R^(ii);

R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv);

R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;

m is 1 to 6;

n is 0 to 4; and

A is either a group of the formula (a) or (b):

whereinR⁴ is is H or C₁₋₆-alkyl;R⁵ is aryl optionally substituted by halo;or a pharmaceutically acceptable salt thereof.

A further embodiment of the invention includes compounds of formula (I)as described herein, or pharmaceutically acceptable salts thereof,

with the proviso that compounds with A of group (b) and R¹=R²=R³=H; and

compounds with A of group (b) and R²═OH, C₁₋₆-alkoxy, or benzyloxy atthe 5-position of the indole are excluded.

A further embodiment of the invention includes compounds of formula (I)as-described herein, or pharmaceutically acceptable salts thereof,

with the proviso that compounds with A of group (b) and R¹═R²═R³═H; and

compounds with A of group (b) and R²═OH, C₁₋₆-alkoxy,—O—CH₂—C₂₋₆-alkenyl or benzyloxy at the 5-position of the indole areexcluded.

A further embodiment of the invention includes compounds of formula (I)as described herein, or pharmaceutically acceptable salts thereof, withthe proviso that R¹═R²═R³═H is excluded.

Also encompassed by the compounds of formula (I) are the followingcompounds of formula (I-a) according to the invention:

wherein R¹ to R⁵ are as defined hereinabove for formula (I).

Preferred compounds of formula (I-a) are those compounds wherein,

R¹ is H,

C₁₋₆-alkyl,

aryl, 5 or 6 membered heteroaryl, sulfonylaryl, each of which isoptionally substituted by one or more B,

—(CH₂)_(m)—R^(a) wherein R^(a) is:

-   -   CN,    -   NR^(i)R^(ii), or    -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or        6 membered heteroaryl each of which is optionally substituted by        one or more B,

or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:

-   -   C₁₋₆-alkoxy,    -   NR^(i)R^(ii), or    -   4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered        heteroaryl each of which is optionally substituted by one or        more B,        or R¹ and R³ together with the indole ring to which they are        attached form a 5 or 6 membered heterocycloalkyl which is        optionally substituted by ═O;        there is one or more R², wherein each R² is the same or        different,        R² is one or more of H,

OH,

halo,

C₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv), or

C₁₋₆-alkoxy;

R³ is H, or

—(CO)—R^(c), wherein R^(c) is:

-   -   —(CH₂)_(n)—NR^(i)R^(ii),    -   —(CH₂)_(n)—NR^(iii)R^(iv),    -   5 or 6 membered heterocycloalkyl optionally substituted by        C₁₋₆-alkyl, or    -   C₁₋₆-alkyl or aryl, each of which is optionally substituted by        halo;        B is halo,

NH₂,

C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,

C₁₋₆-alkoxy,

C₁₋₆-haloalkoxy,

C₃₋₆-cycloalkyl,

—C(O)O—C₁₋₆-alkyl, or

—(CR^(iii)R^(iv))_(n)-phenyl, wherein the phenyl is optionallysubstituted by one or more substituent(s) selected from the-groupconsisting of halo, C₁₋₆-alkyl optionally substituted by CN or halo, andC₁₋₆-alkoxy;

R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv);

R^(i) and R^(iv) are each independently H or C₁₋₆-alkyl;

m is 1 to 6;

n is 0 to4;

R⁴ is is H or C₁₋₆-alkyl; and

R⁵ is aryl optionally substituted by halo;

or a pharmaceutically acceptable salt thereof.

Most preferred compounds of formula (I-a) are those compounds wherein,

R¹ is H,

C₁₋₆-alkyl,

phenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolyl,isoxazolyl, pyrazolyl, imidazolyl, or sulfonylphenyl, each of which isoptionally substituted by one or more B,

—(CH₂)_(m)—R^(a) wherein R^(a) is:

-   -   CN,    -   NR^(i)R^(ii), or    -   C₃₋₆-cycloalkyl, oxetanyl, piperazinyl, tetrahydropyranyl,        morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl,        oxazolyl, isoxazolyl, pyrazolyl or imidazolyl, each of which is        optionally substituted by one or more B,

or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:

-   -   C₁₋₆-alkoxy,    -   NR^(i)R^(ii), or    -   oxetanyl, piperidinyl, piperazinyl, morpholinyl or phenyl, each        of which is optionally substituted by one or more B,        or R¹ and R³ together with the indole ring to which they are        attached form a 5 or 6 membered heterocycloalkyl which is        optionally substituted by (CO);        there is one or more R², wherein each R² is the same or        different,        R² is one or more of H, OH, Cl, Br, or C₁₋₆-alkyl optionally        substituted by —NR^(iii)R^(iv), OMe or OEt;        R³ is H, or

—(CO)—R^(c), wherein R^(c) is:

-   -   —(CH₂)_(n)—NR^(i)R^(ii),    -   —(CH₂)_(n)—NR^(iii)R^(iv),    -   oxetanyl, piperidinyl, piperazinyl, or morpholinyl, each of        which is optionally substituted by C₁₋₆-alkyl, or    -   C₁₋₆-alkyl or aryl, each of which is optionally-substituted by        Cl;        B is halo,

NH₂,

C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,

C₁₋₆-alkoxy,

C₁₋₆-haloalkoxy,

C₃₋₆-cycloalkyl,

—C(O)O—C₁₋₆-alkyl,

or —(CR^(iii)R^(iv))_(n)-phenyl, wherein the phenyl is optionallysubstituted by one or more substituent(s) selected from the groupconsisting of halo, C₁₋₆-alkyl optionally substituted by CN or halo, andC₁₋₆-alkoxy;

R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂-C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv);

R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;

m is 1 to 6;

n is 0to4;

R⁴ is is H or C₁₋₆-alkyl; and

R⁵ is aryl optionally substituted by halo;

or a pharmaceutically acceptable salt thereof.

Further preferred according to the invention are compounds of formula(I-a), wherein R¹ is H,

C₁₋₆-alkyl,

phenyl, optionally substituted by one or more B,

—(CH₂)_(m)—R^(a) wherein R^(a) is NR^(i)R^(ii), or

—(CH₂)_(n)—(CO)—R^(b), wherein R^(b) is NR^(i)R^(ii);

there is one or more R², wherein each R² is the same or different,

R² is one or more of H, Cl, Br, or C₁₋₆-alkyl;

R³ is H, or

—(CO)—R^(c), wherein R^(c) is:

-   -   —(CH₂)_(n)—NR^(i)R^(ii),    -   —(CH₂)_(n)—NR^(iii)R^(iv), or    -   C₁₋₆-alkyl, optionally substituted by Cl;        B is halo,        R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl, or        C₁₋₆-alkyl-NR^(iii)R^(iv);        R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;        m is 1 to 6;        n is 0 to 4;        R⁴ is is H or C₁₋₆-alkyl; and        R⁵ is aryl optionally substituted by halo;        or a pharmaceutically acceptable salt thereof.

Further preferred are compounds of formula (I-a) according to any one ofthe embodiments as described hereinabove, wherein R² is one or twohalogen atom(s) and R¹, R³, R⁴ and R⁵ are as described herein.

Further preferred are compounds of formula (I-a) according to any one ofthe embodiments as described hereinabove, wherein R² is a halogen atomat the 6-position of the indole. Preferably, the halogen atom at the6-position of the indole is Cl.

Further preferred are compounds of formula (I-a) according to any one ofthe embodiments as described hereinabove, wherein one R² is C₁₋₆-alkylor halogen atom at the 5-position of the indole, and one R² is a halogenatom at the 6-position of the indole. Preferably, R² at the 5-positionof the indole is F or Me, and R² at the 6-position of the indole is Cl.

Further preferred are compounds of formula (I-a) according to any one ofthe embodiments as described hereinabove, wherein R³ is C₁₋₆-alkyl.

Further preferred are compounds of formula (I-a) according to any one ofthe embodiments as described hereinabove, wherein R³ is C₁₋₆-alkyl andR² is H.

Further preferred are compounds of formula (I-a) according to any one ofthe embodiments as described hereinabove, wherein either R³ isC₁₋₆-alkyl and R² is H or R³ is H and R² is a halogen, and in particularCl, in the 6-position of the indole.

The following compounds are encompassed by present invention:

-   2-[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;-   8-[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carbonyl]-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   2-[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-N-methyl-acetamide;-   8-(1-Benzyl-6-chloro-1H-indole-3-carbonyl)-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   8-[6-Chloro-1-(3-chloro-2-fluoro-benzyl)-1H-indole-3-carbonyl]-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   8-[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carbonyl]-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   2-[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamide;-   8-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   8-[(1-benzyl-2-methyl-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;-   8-(6-Chloro-1H-indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;-   2-[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-acetamide;-   8-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-1-(4-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   8-(1H-Indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;    and-   8-[(6-Chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.

Also encompassed by the compounds of formula (I) are the followingcompounds of formula (I-b) according to the invention:

wherein R¹ to R³ are as defined hereinabove for formula (I).

Preferred compounds of formula (I-b) are those compounds wherein,

R¹ is H,

C₁₋₆-alkyl,

aryl, 5 or 6 membered heteroaryl, or sulfonylaryl, each of which isoptionally substituted by one or more B,

—(CH₂)_(m)—R^(a) wherein R^(a) is:

-   -   CN,    -   NR^(i)R^(ii), or    -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or        6 membered heteroaryl, each of which is optionally substituted        by one or more B,

or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:

-   -   C₁₋₆-alkoxy,    -   NR^(i)R^(ii), or    -   4 to 7 membered-heterocycloalkyl, aryl, each of which is        optionally substituted by one or more B,        or R¹ and R³ together with the indole ring to which they are        attached form a 5 or 6 membered heterocycloalkyl which        is-optionally substituted by ═O;        there is one or more R², wherein each R² is the same or        different,        R² is one or more H, halo, or C₁₋₆-alkyl optionally substituted        by —NR^(iii)R^(iv);        R³is H, or

—(CO)—R^(c), wherein R^(c) is:

-   -   —(CH₂)_(n)—NR^(i)R^(ii),    -   —(CH₂)_(n)—NR^(iii)R^(iv),    -   5 or 6 membered heterocycloalkyl optionally substituted by        C₁₋₆-alkyl, or    -   C₁₋₆-alkyl or aryl, each of which is optionally substituted by        halo,        B is halo,

NH₂,

C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,

C₁₋₆-alkoxy,

C₁₋₆-haloalkoxy,

C₃₋₆-cycloalkyl,

—C(O)O—C₁₋₆-alkyl,

or —(CR^(iii)R^(iv))_(n)-phenyl, wherein the phenyl is optionallysubstituted by one or more substituent(s) selected from the groupconsisting of halo, C₁₋₆-alkyl optionally substituted by CN or halo, andC₁₋₆-alkoxy;

R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv);

R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;

m is 1 to 6; and

n is 0 to 4;

or a pharmaceutically acceptable salt thereof.

Most preferred compounds of formula (I-b) are those compounds wherein,R¹ is H,

C₁₋₆-alkyl,

phenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolyl,isoxazolyl, pyrazolyl, imidazolyl, or sulfonylphenyl, each of which isoptionally substituted by one or more B,

—(CH₂)_(m)—R^(a) wherein R^(a) is:

-   -   CN,    -   NR^(i)R^(ii), or    -   C₃₋₆-cycloalkyl, oxetanyl, piperazinyl, tetrahydropyranyl,        morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl,        oxazolyl, isoxazolyl, pyrazolyl or imidazolyl, each of which is        optionally substituted by one or more B,

or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:

-   -   C₁₋₆-alkoxy,    -   NR^(i)R^(ii), or    -   oxetanyl, piperidinyl, piperazinyl, morpholinyl or phenyl, each        of which is optionally substituted by one or more B,        or R¹ and R³ together with the indole ring to which they are        attached form a 5 or 6 membered heterocycloalkyl which is        optionally substituted by ═O;        there is one or more R², wherein each R² is the same or        different,        R² is one or more H, Cl, Br, or C₁₋₆-alkyl optionally        substituted by —NR^(iii)R^(iv);        R³ is H, or

—(CO)—R^(c), wherein R^(c) is:

-   -   —(CH₂)_(n)—NR^(i)R^(ii),    -   —(CH₂)_(n)—NR^(iii)R^(iv),    -   oxetanyl, piperidinyl, piperazinyl, or morpholinyl, each of        which-is optionally substituted by C₁₋₆-alkyl, or    -   C₁₋₆-alkyl or aryl, each of which is optionally substituted by        Cl;        B is halo,

NH₂,

C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,

C₁₋₆-alkoxy,

C₁₋₆-haloalkoxy,

C₃₋₆-cycloalkyl,

—C(O)O—C₁₋₆-alkyl, or

—(CR^(iii)R^(iv))_(n)-phenyl, wherein the phenyl is optionallysubstituted by one or more substituent(s) selected from the groupconsisting of halo, C₁₋₆-alkyl optionally substituted by CN or halo, andC₁₋₆-alkoxy;

R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv);

R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;

m is 1 to 6; and

n is 0to 4;

or a pharmaceutically acceptable salt thereof.

Further preferred are compounds of formula (I-b) according to any one ofthe embodiments as described hereinabove, wherein R₂ is one or twohalogen atom(s).

Further preferred are compounds of formula (I-b) according to any one ofthe embodiments as described hereinabove, wherein R² is a halogenatom-at the 6-position of the indole. Preferably, the halogen atomat-the 6-position of the indole is Cl.

Further preferred are compounds of formula (I-b) according to any one ofthe embodiments as described hereinabove, wherein one R² is C₁₋₆ alkylor halogen atom at the 5-position of the indole, and one R² is a halogenatom at the 6-position of-the indole. Preferably, R² at the 5-positionof the indole is F or Me, and R²at the 6-position of the indole is Cl.

Further preferred are compounds of formula (I-b) according to any one ofthe embodiments as described hereinabove, wherein R³ is C₁₋₆-alkyl.

Further preferred are compounds of formula (I-b) according to-any one ofthe embodiments as described hereinabove, wherein R³ is C₁₋₆-alkyl andR² is H.

Further preferred are compounds of formula (I-b) according to any one ofthe embodiments as described hereinabove, wherein either R³ isC₁₋₆-alkyl and R² is H or R³ is H and R is a halogen, and in particularCl, in the 6-position of the indole.

The invention encompasses for example the following compounds:(1-Benzyl-2-methyl-1H-indol-3-yl)-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone;and8-[(6-chloro-1H-indol-3-yl)carbonyl]-1,4-dioxa-8-azaspiro[4.5]decane.

The invention also encompasses methods for the treatment ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion-of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders which compriseadministering a therapeutically effective amount of a compound offormula (i), (I-a), or (I-b) or a pharmaceutically acceptable saltthereof.

The invention also encompasses pharmaceutical compositions comprising acompound of formula (I), (I-a) or (I-b) which pharmaceuticalcompositions are useful for the treatment of dysmenorrhea, hypertension,chronic heart failure, inappropriate secretion of vasopressin, livercirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxietyand depressive disorders.

The invention also encompasses processes for the preparation ofcompounds of formula (I), (I-a) or (I-b).

In a certain embodiment, the compounds of formula (I) of theinvention-can be prepared according to a process comprising reacting acompound of formula (II):

with a compound of formula A-H, to obtain a compound of formula (I),wherein R¹, R², R³ and A are as defined hereinabove for formula (I). Thesynthesis is optionally performed in an inert solvent.

Amide couplings as such are known to the person skilled in the art.Optionally, the carboxylic acid II is activated, either in a first stepor in situ during amide synthesis. Activated species of carboxylic acidII are for example acid chlorides, anhydrides or mixed anhydrides,azides, or activated esters. Examples for activated esters arepentachloro- or pentafluorophenole esters of carboxylic acid II.Activation reagents for activation of the carboxylic acid during amidesynthesis are for example carbodiimides which form activated esters asintermediates, namely the respective O-acyl-ureas. Examples forcarbodiimides are N,N′-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) orN,N′-diisopropylcarbodiimide (DIC), each of which can optionally becombined with coupling reagents such as N-hydroxybenzotriazole (HOBt),O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP) and the like.A further reagent for activation is N,N′-carbonyl-di-imidazole, formingthe respective acid imidazolide as an activated intermediate.

This process is described more in details in general scheme andprocedure A hereinafter.

In another embodiment, the compounds of formula (I) of the invention canbe prepared according to a process comprising reacting a compound offormula (I-1):

with a compound of formula R¹—X, to obtain a compound of formula (I),wherein X is halo, preferably Cl, R¹ and R⁴ are as defined hereinabovefor formula-(I) but are different from H and R² and R³ are as definedhereinabove for formula (I). This process is described more in detailsin general scheme and procedure B hereinafter.

In still another embodiment, the compounds of formula (I-a) of theinvention can be prepared according to a process comprising reacting acompound of formula (I-a l):

with a compound of formula R⁴—X, to obtain a compound of formula (I-a),wherein X is halo, preferably Cl, R¹, R⁴ and R⁵ are as definedhereinabove for formula (I) but are different from H and R² and R³ areas defined hereinabove for formula (I). This process is described morein details in general scheme and procedure C hereinafter.

As already mentioned hereinabove, the aforementioned processes aredescribed more in details with the following general schemes andprocedures A to C. General scheme and procedure D show how to prepareuseful inter-mediates of formula (II).General Scheme A

Compounds of formula (I) can be prepared via an amide coupling betweenan indole 3-carboxylic acid-(II) and a piperidine (A-H). Indole3-carboxylic acids (II) are either commercially available or readilyprepared using a procedure described in. J. Med. Chem. 1991, 34, 140, orprepared following the general scheme D. The piperidine derivatives A-Hare either commercially available or prepared using publishedprocedures.General Scheme B

Compounds of formula (1-2) (compounds of formula (I) wherein R¹ and R⁴are both different from H), can be prepared by alkylation of the indolederivative of formula (I-1), (compounds of formula (I) wherein R¹ is Hand R⁴ is different from H), with an electrophile of formula R¹—X(commercially available, wherein X is halo, preferably Cl or Br) usingstandard procedures. Derivatives (I-1) are prepared using the methoddescribed in the general scheme A.General Scheme C

Compounds of formula (I-a2) (compounds of formula (I-a) wherein R¹ andR⁴ both different from H), can be prepared by an alkylation of aderivative (I-a1) (compounds of formula (I-a), wherein R⁴ is H and R¹ isdifferent from H) with an electrophile of formula R⁴—X (commerciallyavailable, wherein X is halo, preferably Cl or Br) using standardprocedures. Derivatives of formula (I-a1) are prepared using the methoddescribed in-the general scheme AGeneral Scheme D

The treatment of an indole derivative of formula (III) with thetrifluoroacetic anhydride in DMF afforded the intermediate of formula(IV) which can be then hydrolysed with an aqueous sodium hydroxidesolution to give the 3-carboxylic acid-indole derivative of formula(II-a). Alternatively, the compound of formula (IV) could react with anelectrophile of formula R¹—X (commercially available, wherein X is halo,preferably Cl or Br and R¹ is other than H) to give the compound offormula (V), which is then converted to the corresponding carboxylicacid derivative of formula (I-b) with NaH/H₂O in DMF (see J. Org Chem.,1993, 10, 2862).

V1a Activity

Material & Method:

The human V1a receptor was cloned by RT-PCR from total human liver RNA.The coding sequence was subcloned in an expression vector aftersequencing to confirm the identity of the amplified sequence. Todemonstrate the affinity of the compounds of formula (I) of the presentinvention to the human V1a receptor binding studies were performed. Cellmembranes were prepared from HEK293 cells transiently transfected withthe expression vector and grown in 20 liter fermenters with thefollowing protocol.

50 g of cells are resuspended in 30 ml freshly prepared ice cold Lysisbuffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2 adjusted to pH=7.4+completecocktail of protease inhibitor (Roche Diagnostics)). Homogenized withPolytron for 1 min and sonicated on ice for 2×2 minutes at 80% intensity(Vibracell sonicator). The preparation is centrifuged 20 min at 500 g at4° C., the pellet is discarded and the supernatant centrifuged 1 hour at43,000 g at 4° C. (19,000 rpm). The pellet is resuspended in 12.5 mlLysis buffer+12.5 ml Sucrose 20% and homogenized using a Polytron for1-2 min. The protein concentration is determined by the Bradford method,and aliquots are stored at −80° C. until use. For binding studies 60 mgYttrium silicate SPA beads (Amersham) are mixed with an aliquot ofmembrane in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mMCaCl2, 10 mM MgCl2) for 15 minutes with mixing. 50 ul of bead/membranemixture is then added to each well of a 96 well plate, followed by 50 ulof 4 nM 3H-Vasopressin (American Radiolabeled Chemicals). For totalbinding measurement 100 ul of binding buffer are added to the respectivewells, for non-specific binding 100 ul of 8.4 mM cold vasopressin andfor compound testing 100 ul of a serial dilution of each compound in 2%DMSO. The plate is incubated 1 h at room temperature, centrifuged 1 minat 1000 g and counted on a Packard Top-Count. Non-specific bindingcounts are subtracted from each well, and data is normalized to themaximum specific binding set at 100%. To calculate an IC 50 the curve isfitted using a non-linear regression model (XLfit), and the Ki iscalculated using the Cheng-Prussoff equation. Compound of Example Ki(nM) 1 368 2 367 7 156 8 37 9 21 10 14 11 45 13 73 14 184 15 424 16 284

The present invention also provides pharmaceutical compositionscontaining compounds of formula (I), (I-a) or (I-b) or theirpharmaceutically acceptable acid addition salts, and a pharmaceuticallyacceptable carrier. Such pharmaceutical compositions can be in the formof tablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic and organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc canbe used as such excipients e.g. for tablets, dragées and hard gelatincapsules. Suitable excipients for soft gelatin capsules are e.g.vegetable oils, waxes, fats, semi-solid and liquid polyols etc. Suitableexcipients for the manufacture of solutions and syrups are e.g. water,polyols, saccharose, invert sugar, glucose etc. Suitable excipients forinjection solutions are e.g. water, alcohols, polyols, glycerol,vegetable oils etc. Suitable excipients for suppositories are e.g.natural or hardened oils, waxes, fats, semi-liquid or liquid polyolsetc.

Moreover, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The invention also provides a method for preparing compositions of theinvention which comprises bringing one or more compounds of formula I,I-a, or I-b and/or pharmaceutically acceptable acid addition saltsthereof and, if desired, one or more other therapeutically valuablesubstances into a galenical administration form together with one ormore therapeutically inert carriers.

The compounds and compositions of the present invention can beadministered in-a conventional manner, for example, orally, rectally, orparenterally. The compounds of the invention can be administered orally,for example, in the form of tablets, coated tablets, dragées, hard andsoft-gelatin capsules, solutions, emulsions, or suspensions. Thecompounds of the invention can be administered rectally, for example, inthe form of suppositories or parenterally, for example, in the form ofinjectable solutions.

Compounds of formula (I) have good activity on the V1a receptor.Therefore, the invention provides methods for the treatment ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders. Such methodscomprise administering a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof. Thepreferred indications with regard to the present invention are thetreatment of anxiety and depressive disorders.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 10 to 1000 mg per person of acompound of general formula (I), (I-a) or (I-b) should be appropriate,although the above upper limit can also be exceeded when necessary.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

EXAMPLE A

Tablets of the following composition are manufactured in the usualmanner: mg/tablet Active substance 5 Lactose 45 Corn starch 15Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight 100

EXAMPLE B

Capsules of the following composition are manufactured: mg/capsuleActive substance 10 Lactose 155 Corn starch 30 Talc 5 Capsule fillweight 200

The active substance, lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer, the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into hard gelatin capsules.

EXAMPLE C

Suppositories of the-following composition are manufactured: mg/supp.Active substance 15 Suppository mass 1285 Total 1300

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered activesubstance is added thereto and stirred until it has dispersedcompletely. The mixture is poured into suppository moulds of suitablesize, left to cool; the suppositories are then removed from the mouldsand packed individually in wax paper or metal foil.

EXAMPLES

Where journal references are cited in the examples, the example wasperformed using the starting material listed with the reactants andconditions cited in the reference. All procedures in such references arewell known to those of ordinary skill in the art. All journal referencescited herein are incorporated by reference.

General Procedure I—Amide Coupling:

To a stirred solution of an indole-3-carboxylic acid derivative of type(II) (1 mmol) in 10 ml CH₂Cl₂ was added (1.3 mmol) EDC, (1.3 mmol) HOBt,(1.3 mmol) Et₃N and (1 mmol) of the amine derivative (A-H). The mixturewas stirred overnight at room temperature and then poured onto water andextracted with CH₂Cl₂. The combined organic phases were dried overNa₂SO₄ and concentrated in vacuo. Flash chromatography or preparativeHPLC afforded a compound of formula (I).

General Procedure II—Alkylation:

To a stirred solution of a derivative of general formula (I-1) in DMFwas added 2.1 eq. NaH (60% in oil). The mixture was stirred at roomtemperature for 30 min. and then the electrophilic reactant R¹—X (1.1eq.) was added. The mixture was stirred an additional 14 hours at 60 °C. and then poured onto water and extracted with ethyl acetate. Thecombined organic phases were dried over Na₂SO₄ and concentrated invacuo. Purification by preparative HPLC afforded the correspondingderivatives of general formula (I-2).

Acid Intermediates of Formula II Acid 11-Benzyl-2-methyl-1H-indole-3-carboxylic acid

To a stirred solution of 0.50 g (3.10 mmol)2-methyl-1H-indole-3-carboxylic acid (described in J. Heterocyclic Chem.1977, 14, 1123) in 5 ml DMF were added 0.27 g (6.75 mmol) of NaH (60% inoil). The mixture was stirred at room temperature for 30 min. and then0.39 ml (3.28 mmol) of benzyl bromid were added. The mixture was stirredfor one additional hour and then poured onto water and extracted withethyl acetate. The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo. Crystallization from Et₂O afforded1-benzyl-2-methyl-1H-indole-3-carboxylic acid.

Acid 2 6-Chloro-1H-indole-3-carboxylic acid

a) 1-(6-Chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

To a solution of 15.0 g (98.9 mmol) 6-chloroindole in 150 ml dryN,N-dimethylformamide were added dropwise under argon 15.8 ml (114 mmol)trifluoroacetic anhydride at 0 ° C. After stirring at 0 ° C. for 2 hanother portion of 15.8 ml (114 mmol) trifluoroacetic anhydride wasadded, and stirring was continued for 30 min. Quenching with saturatedaqueous sodium carbonate solution was followed by extraction with threeportions of ethyl acetate. The combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was triturated intert.-butyl methyl ether. Filtration gave 20.4 g (82%) of the titlecompound as a white solid. The mother liquor was concentrated in vacuoand triturated in tert.-butyl methyl ether to give another portion of1.2 g (5%) of the title compound.

MS m/e (%): 246 (M-H⁺, 100)

b) 6-Chloro-1H-indole-3-carboxylic acid

A solution of 21.6 g (87.2 mmol)1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 110 ml of a 4 Maqueous solution of potassium hydroxide was heated at reflux for 2 h.After cooling to 0 ° C. neutralisation with 36.7 ml of a concentratedaqueous hydrochloric acid solution a white solid precipitated from thesolution. The solid was collected by filtration and washed with water.Drying in high vacuo at 80 ° C. gave 16.4 g (96%) of the title compoundas a light yellow solid.

MS m/e (%): 194 (M-H⁺, 100)

Examples of Compounds of Formula (I-a) Example 18-[(1-Benzyl-2-methyl-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

Amide coupling according to general procedure I:

-   Amine: 3-Methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one    (described in App. Radiat. Isot. 1995,46,911;-   Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid;    ES-MS m/e (%): 493.5 (M+H⁺).

Example 28-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

Amide coupling according to-general procedure I:

-   Amine: 1-Phenyl-1,3,8-triaza-spiro [4.5]decan-4-one    (commercially-available);-   Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid;    ES-MS m/e (%): 479.4 (M+H⁺).

Example 3

8-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-1-(4-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one

Amide coupling according to general procedure I:

-   Amine: 1-(4-Chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one    (described in WO2005040166A1);-   Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid;    ES-MS m/e (%): 513.1(M+H⁺).

Example 48-(6-Chloro-1H-indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

Amide coupling according to general procedure I:

-   Amine: 1-Phenyl-1,3,8-triaza-spiro[4.5]decan4-one (commercially    available);-   Acid: 6-Chloro-1H-indole-3-carboxylic acid;    ES-MS m/e (%): 409 (M+H⁺).

Example 58-(1H-Indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

Amide coupling according to general procedure I:

-   Amine: 1-Phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (commercially    available);-   Acid: 1H-Indole-3-carboxylic acid (commercially available);    ES-MS m/e (%): 375.3 (M+H⁺).

Example 6

8-[(6-Chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

Following the general procedure I, the couplingof3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (described inApp. Radiat. Isot. 1995,46,911) with 6-chloro-1H-indole-3-carboxylicacid gave the title compound.

ES-MS m/e (%): 423.5 (M+H⁺).

Example 78-({6-Chloro-1-[2-(dimethylamino)ethyl]-1H-indol-3-yl}carbonyl)-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

Following the general procedure II, the coupling of8-[(6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onewith (commercially available) (2-chloro-ethyl)-dimethyl-amine gave thetitle compound.

ES-MS m/e (%): 494.2 (M+H⁺).

Example 82-{6-Chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)carbonyl]-1H-indol-1-yl}-N-methylacetamide

Following the general procedure II, the coupling of8-[(6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onewith (commercially available) 2-chloro-N-methyl-acetamide gave the titlecompound.

ES-MS m/e (%): 494.2 (M+H⁺).

Example 98-{[6-Chloro-1-(3,5-difluorobenzyl)-1H-indol-3-yl]carbonyl}-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

Following the general procedure II, the coupling of8-[(6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onewith (commercially available) 1-chloromethyl-3,5-difluoro-benzene gavethe title compound.

ES-MS m/e (%): 549.2 (M+H⁺).

Example 102-{6-Chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide

Following the general procedure II, the coupling of8-[(6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onewith (commercially available) 2-chloro-N,N-dimethyl-acetamide gave thetitle compound.

ES-MS m/e (%): 508.2 (M+H⁺).

Example 118-[(1-Benzyl-6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

Following the general procedure II, the coupling of8-[(6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onewith (commercially available) benzyl chloride gave the title compound.

ES-MS m/e (%): 513.2 (M+H⁺).

Example 122-{6-Chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)carbonyl]-1H-indol-1-yl}acetamide

Following the general procedure II, the coupling of8-[(6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onewith (commercially available) 2-chloro-acetamide gave the titlecompound.

ES-MS m/e (%): 480.2 (M+H⁺).

Example 138-{[6-Chloro-1-(3-chloro-2-fluorobenzyl)-1H-indol-3-yl]carbonyl}-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

Following the general procedure, the coupling of8-[(6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onewith (commercially-available) 1-chloro-3-chloromethyl-2-fluoro-benzenegave the title compound.

ES-MS m/e (%): 565.2 (M+H⁺).

Example 142-{6-Chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)carbonyl]-1H-indol-1-yl}-N-[2-(dimethylamino)ethyl]acetamide

a)[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-aceticacid

Following the general procedure II, the coupling of8-[(6-chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-onewith (commercially available) bromo-acetic acid gave the title compound.

ES-MS m/e (%): 479.1 (M−H⁺).

b)2-{6-Chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)carbonyl]1H-indol-1-yl}-N-[2-(dimethylamino)ethyl]acetamide

A solution of[6-chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]-decane-8-carbonyl)-indol-1-yl]-aceticacid in DMF was treated sequentially with 1 eq. ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, 1 eq. of N,N-diisopropylethylamine and 1 eq. ofN,N-dimethylethylenediamine. The mixture was shaken at room temperaturefor 12 h, concentrated and purified by prep. HPLC to give the titlecompound.

ES-MS m/e (%): 551.2 (M+H⁺).

Examples of Compounds of Formula (I-b) Example 15(1-Benzyl-2-methyl-1H-indol-3-yl)-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone

Amide coupling according to general procedure I:

-   Amine: 1,4-Dioxa-8-aza-spiro[4.5]decane (commercially available);-   Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid;    ES-MS m/e (%): 391.5 (M+H⁺).

Example 168-[(6-Chloro-1H-indol-3-yl)carbonyl]-1,4-dioxa-8-azaspiro[4.5]decane

Amide coupling according to general procedure I:

-   Amine: 1,4-Dioxa-8-aza-spiro[4.5]decane (commercially available);-   Acide: 6-chloro-1H-indole-3-carboxylic acid.

1. A compound of formula (I):

wherein R¹ is H, C₁₋₆-alkyl, aryl, 5 or 6 membered heteroaryl orsulfonylaryl, each of which is optionally substituted by one or more B,—(CH₂)_(m)—R^(a) wherein R^(a) is: CN, NR^(i)R^(ii), or C₃₋₆-cycloalkyl,4 to 7-membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl,each of which is optionally substituted by one or more B, or—(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl, —(CH₂)_(m)—NR^(iii)R^(iv),NR^(i)R^(ii), or C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl,aryl, or 5 or 6 membered heteroaryl, each of which is optionallysubstituted by one or more B, or R¹ and R³ together with the indole ringto which they are attached form a 5 or 6 membered heterocycloalkyl whichis optionally substituted by ═O; there is one or more R², wherein eachR² is the same or different, R² is one or more H, OH, halo, CN, nitro,C₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv), C₁₋₆-alkoxy,—O—CH₂—C₂₋₆-alkenyl, or benzyloxy, or two R² together with the indolering to which they are attached form an oxo or dioxo bridge; R³ is H,halo, or —(CO)—R^(c), wherein R^(c) is: C₁₋₆-alkyl,—(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), or 5 or 6 memberedheterocycloalkyl optionally substituted by C₁₋₆-alkyl, or C₁₋₆-alkyl oraryl, each of which is optionally substituted by halo,—O(CO)—C₁₋₆-alkyl, or —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyloptionally substituted by halo or nitro, or R^(d) is aryl or a 5 or 6membered heteroaryl, each of which is optionally substituted by halo,nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl; B is halo, CN, NR^(i)R^(ii),C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)NR^(i)R^(ii), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, —S(O)₂—NR^(i)R^(ii),or (CR^(iii)R^(iv))_(n)-phenyl or (CR^(iii)R^(iv))_(n)-5 or 6 memberedheteroaryl, wherein the phenyl or 5 or 6 membered heteroaryl moiety isoptionally substituted by one or more substituent(s) selected from thegroup consisting of halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionallysubstituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and —S(O)₂—NR^(i)R^(ii); R^(i) andR^(ii) are each independently H, C₁₋₆-alkyl, —C₁₋₆-alkyl-NR^(iii)R^(iv),—(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl,—S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv); R^(iii) and R^(iv) are eachindependently H or C₁₋₆-alkyl; m is 1 to 6; n is 0 to 4; and A is eithera group of the formula (a) or (b):

wherein R⁴ is is H or C₁₋₆-alkyl; and R⁵ is aryl optionally substitutedby halo; or a pharmaceutically acceptable salt thereof.
 2. The compoundof claim 1, wherein R¹ is H, C₁₋₆-alkyl, aryl, 5 or 6 memberedheteroaryl or sulfonylaryl each of which is optionally substituted byone or more B, —(CH₂)_(m)—R^(a) wherein R^(a) is: CN, OR^(i),NR^(i)R^(ii), or C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl,aryl, or 5 or 6 membered heteroaryl, each of which is optionallysubstituted by one or more B, or —(CH₂)_(n)—(CO)—R^(b) or—(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is: C₁₋₆-alkyl, C₁₋₆-alkoxy,C₃₋₆-cycloalkyl, —(CH₂)_(m)—NR^(iii)R^(iv), NR^(i)R^(ii) orC₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6membered heteroaryl, each of which is optionally substituted by one ormore B, or R¹ and R³ together with the indole ring to which they areattached form a 5 or 6 membered heterocycloalkyl which is optionallysubstituted by ═O; there is one or more R², wherein each R² is the sameor different, R² is one or more H, OH, halo, CN, nitro, or C₁₋₆-alkyloptionally substituted by —NR^(iii)R^(iv), C₁₋₆-alkoxy,—O—CH₂—C₂₋₆-alkenyl, or benzyloxy, or two R² together with the indolering to which they are attached form an oxo or dioxo bridge, R³ is H,halo, or —(CO)—R^(c), wherein R^(c) is: C₁₋₆-alkyl,—(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), or 5 or 6 memberedheterocycloalkyl optionally substituted by C₁₋₆-alkyl, or C₁₋₆-alkyl oraryl, each of which is optionally substituted by halo,—O(CO)—C₁₋₆-alkyl, or —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyloptionally substituted by halo or nitro, or R^(d) is aryl or a 5 or 6membered heteroaryl, each of which is optionally substituted by halo,nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl; B is halo, CN, NR^(i)R^(ii),C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)NR^(i)R^(ii), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, —S(O)₂—NR^(i)R^(ii),or (CR^(iii)R^(iv))_(n)-phenyl, or (CR^(iii)R^(iv))_(n)-5 or 6 memberedheteroaryl wherein the phenyl or 5 or 6 membered heteroaryl moiety isoptionally substituted by one or more substituent(s) selected from thegroup consisting of halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionallysubstituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and —S(O)₂—NR^(i)R^(ii); R^(i) andR^(ii) are each independently H, C₁₋₆-alkyl, C₁₋₆-alkyl-NR^(iii)R^(iv),—(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl,—S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv); R^(iii) and R^(iv) are eachindependently H or C₁₋₆-alkyl; m is 1 to 6; n is 0 to 4; and A is eithera group of the formula (a) or (b):

wherein R⁴ is is H or C₁₋₆-alkyl; and R⁵ is aryl optionally substitutedby halo; or a pharmaceutically acceptable salt thereof.
 3. A compound ofclaim 1, or a pharmaceutically acceptable salt thereof, with the provisothat compounds wherein A is group (b) and R¹═R²═R³═H; and compoundswherein A of group (b) and R² =OH, C₁₋₆-alkoxy, or benzyloxy at the5-position of the indole are excluded.
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, with the proviso thatcompounds wherein A is group (b) and R¹═R²═R³═H; and compounds wherein Aof group (b) and R²═OH, C₁₋₆-alkoxy, —O—CH²—C₂₋₆alkenyl or benzyloxy atthe 5-position of the indole are excluded.
 5. The compound of claim 1having formula (I-a),


6. The compound of claim 5, wherein R¹ is H, C₁₋₆-alkyl, aryl, 5 or 6membered heteroaryl, sulfonylaryl, each of which is optionallysubstituted by one or more B, —(CH₂)_(m)—R^(a) wherein R^(a) is: CN,NR^(i)R^(ii), or C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl,aryl, or 5 or 6 membered heteroaryl each of which-is optionallysubstituted by one or more B, or —(CH₂)_(n)—(CO)—R^(b) or—(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is: C₁₋₆-alkoxy, NR^(i)Ru^(ii), or4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryleach of which is optionally substituted by one or more B, or R¹ and R³together with the indole ring to which they are attached form a 5 or 6membered heterocycloalkyl which is optionally substituted by ═O; thereis one or more R², wherein each R² is the same or different, R² is oneor more of H, OH, halo, C₁₋₆-alkyl optionally substituted by—NR^(iii)R^(iv), or C₁₋₆-alkoxy; R³ is H, or —(CO)—R^(c), wherein R^(c)is: —(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), 5 or 6 memberedheterocycloalkyl optionally substituted by C₁₋₆-alkyl, or C₁₋₆-alkyl oraryl, each of which is optionally substituted by halo; B is halo, NH₂,C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C—₁₋₆-alkyl, or—(CR^(iii)R^(iv))_(n)-phenyl, wherein the phenyl is optionallysubstituted by one or more substituent(s) selected from thegroup-consisting of halo, C₁₋₆-alkyl optionally substituted by CN orhalo and C₁₋₆-alkoxy; R^(i) and R^(ii) are each independently H,C₁₋₆-alkyl, C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl,—C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or—S(O)₂—NR^(iii)R^(iv); R^(iii) and R^(iv) are each independently H orC₁₋₆-alkyl; m is 1 to 6; n is 0 to 4; R⁴ is is H or C₁₋₆-alkyl; and R⁵is aryl optionally substituted by halo; or a pharmaceutically acceptablesalt thereof.
 7. The compound of formula (I-a) according to claim 5,wherein R¹ is H, C₁₋₆-alkyl, phenyl, thiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, orsulfonylphenyl, each of which is optionally substituted by one or moreB, —(CH₂)_(m)—R^(a) wherein R^(a) is: CN, NR^(i)R^(ii), orC₃₋₆-cycloalkyl, oxetanyl, piperazinyl, tetrahydropyranyl, morpholinyl,phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl,pyrazolyl or imidazolyl, each of which is optionally substituted by oneor more B, or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)n—(SO₂)—R^(b), whereinR^(b) is: C₁₋₆-alkoxy, NR^(i)R^(ii), or oxetanyl, piperidinyl,piperazinyl, morpholinyl or phenyl, each of which is optionallysubstituted by one or more B, or R¹ and R³ together with the indole ringto which they are attached form a 5 or 6 membered heterocycloalkyl Whichis optionally substituted by (CO); there is one or more R², wherein eachR² is the same or different, R² is one or more of H, OH, Cl, Br, orC₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv), OMe or OEt; R³ isH, or —(CO)—R^(c), wherein R^(c) is: —(CH₂)_(n)—NR^(i)R^(ii),—(CH₂)_(n)—NR^(iii)R^(iv), oxetanyl, piperidinyl, piperazinyl, ormorpholinyl, each of which is optionally substituted by C₁₋₆-alkyl, orC₁₋₆-alkyl or aryl, each of which is optionally substituted by Cl; B ishalo, NH₂, C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, or—(CR^(iii)R^(iv))_(n)-phenyl, wherein the phenyl is optionallysubstituted by one or more substituent(s) selected from the groupconsisting of halo, C₁₋₆-alkyl optionally substituted by CN or halo, andC₁₋₆-alkoxy; R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆allkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv); R^(iii)and R^(iv) are each independently H or C₁₋₆-alkyl; m is 1 to 6; n is 0to 4; R⁴ is is H or C₁₋₆-alkyl; and R⁵ is aryl optionally substituted byhalo; or a pharmaceutically acceptable salt thereof.
 8. The compound ofclaim 5, wherein R¹ is H, C₁₋₆-alkyl, phenyl, optionally substituted byone or more B, —(CH₂)_(m)—R^(a) wherein R^(a) is NR^(i)R^(ii), or—(CH₂)_(n)—(CO)—R^(b), wherein R^(b) is NR^(i)R^(ii); there is one ormore R², wherein each R² is the same or different, R² is one or more ofH, Cl, Br, or C₁₋₆-alkyl; R³is H, or —(CO)—R^(c), wherein R^(c) is:—(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), or C₁₋₆-alkyl,optionally substituted by Cl; B is halo, R^(i) and R^(ii) are eachindependently H, C₁₋₆-alkyl, or C₁₋₆-alkyl-NR^(iii)R^(iv); R^(iii) andR^(iv) are each independently H or C₁₋₆-alkyl; m is 1 to 6; n is 0 to 4;R⁴ is is H or C₁₋₆-alkyl; and R⁵ is aryl optionally substituted by halo;or a pharmaceutically acceptable salt thereof.
 9. The compound of claim5, wherein R² is one or two halogen atom(s).
 10. The compound of claim9, wherein R² is a halogen atom at the 6-position of the indole.
 11. Thecompound of claim 7, wherein R² is Cl at the 6-position of the indole.12. The compound of 5, wherein one R is C₁₋₆-alkyl or halogen atom atthe 5-position of the indole, and one R² is a halogen atom at the6-position of the indole.
 13. The compound of claim 12, wherein the R²at the 5-position of the indole is F or Me and the R² at the 6-positionof the indole is Cl.
 14. The compound of claim 5, wherein R³ isC₁₋₆alkyl.
 15. The compound of claim 14, wherein R² is hydrogen.
 16. Thecompound of claim 5, wherein R³ is C₁₋₆ alkyl and R² is H or wherein R³is hydrogen and R² is halogen.
 17. The compound of claim 16, wherein Ris Cl at the 6-position of the indole.
 18. The compound of claim 1,selected from the-group consisting of:2-[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;8-[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carbonyl]-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;2-[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-N-methyl-acetamide;8-(1-Benzyl-6-chloro-1H-indole-3-carbonyl)-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;8-[6-Chloro-1-(3-chloro-2-fluoro-benzyl)-1H-indole-3-carbonyl]-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;8-[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carbonyl]-3-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;2-[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamide.19. The compound of claim 1, selected from the group consisting of8-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;8-[(1-benzyl-2-methyl-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;8-(6-Chloro-1H-indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;2-[6-Chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-acetamide;8-(1-Benzyl-2-methyl-1H-indole-3-carbonyl)-1-(4-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;8-(1H-Indole-3-carbonyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one;and8-[(6-Chloro-1H-indol-3-yl)carbonyl]-3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.20. The compound of claim 1 having formula (I-b),


21. The compound of claim 20, wherein R¹ is H, C₁₋₆-alkyl, aryl, 5 or 6membered heteroaryl, or sulfonylaryl, each of which is optionallysubstituted by one or more B, —(CH₂)_(m)—R^(a) wherein R^(a) is: CN,NR^(i)R^(ii), or C₃₋₆-cycloalkl, 4 to 7 membered-heterocycloalkyl, aryl,or 5 or 6 membered heteroaryl, each of which is optionally substitutedby one or more B, or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b),wherein R^(b) is: C₁₋₆-alkoxy, NR^(i)R^(ii), or 4 to 7membered-heterocycloalkyl, aryl, each of which is optionally substitutedby one or more B, or R¹ and R³ together with the indole ring to whichthey are attached form a 5 or 6 membered heterocycloalkyl which isoptionally substituted by ═O; there is one or more R², wherein each R²is the same or different, R² is one or more H, halo, or C₁₋₆-alkyloptionally substituted by —NR^(iii)R^(iv); R³ is H, or —(CO)—R^(c),wherein R^(c) is: —(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), 5or 6 membered heterocycloalkyl optionally substituted by C₁₋₆-alkyl, orC₁₋₆-alkyl or aryl, each of which is optionally substituted by halo, Bis halo, NH₂, C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, or—(CR^(iii)R^(iv))_(n)-phenyl, wherein the phenyl is optionallysubstituted by one or more substituent(s) selected from the groupconsisting of halo, C₁₋₆-alkyl optionally substituted by CN or halo, andC₁₋₆-alkoxy; R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O-C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv); R^(iii)and R^(iv) are each independently H or C₁₋₆-alkyl; m is 1 to 6; and n is0 to 4; or a pharmaceutically acceptable salt thereof.
 22. The compoundof claim 21, wherein R¹ is H, C₁₋₆-alkyl, phenyl, thiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,or sulfonylphenyl, each of which is optionally substituted by one ormore B, —(CH₂)_(m)—R^(a) wherein R^(a) is: CN, NR^(i)R^(ii), orC₃₋₆-cycloalkyl, oxetanyl, piperazinyl, tetrahydropyranyl, morpholinyl,phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl,pyrazolyl or imidazolyl, each of which is optionally substituted by oneor more B, or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), whereinR^(b) is: C₁₋₆-alkoxy, NR^(i)R^(ii), or oxetanyl, piperidinyl,piperazinyl, morpholinyl or phenyl, each of which is optionallysubstituted by one or more B, or R¹ and R³ together with the indole ringto which they are attached form a 5 or 6 membered heterocycloalkyl whichis optionally substituted by ═O; there is one or more R², wherein eachR² is the same or different, R² is one or more H, Cl, Br, or C₁₋₆-alkyloptionally substituted by —NR^(iii)R^(iv); R³ is H, or —(CO)—R^(c),wherein R^(c) is: —(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv),oxetanyl, piperidinyl, piperazinyl, or morpholinyl, each of which isoptionally substituted by C₁₋₆-alkyl, or C₁₋₆-alkyl or aryl, each ofwhich is optionally substituted by Cl; B is halo, NH₂, C₁₋₆-alkyloptionally substituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, or—(CR^(iii)R^(iv))_(n)-phenyl, wherein the phenyl is optionallysubstituted by one or more substituent(s) selected from the groupconsisting of halo, C₁₋₆-alkyl optionally substituted by CN or halo, andC₁₋₆-alkoxy; R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv); R^(iii)and R^(iv) are each independently H or C₁₋₆-alkyl; m is 1 to 6; and n is0 to 4; or a pharmaceutically acceptable salt thereof.
 23. The compoundof claim 20, wherein R² is one or two halogen atoms.
 24. The compound ofclaim 20, wherein R² is a halogen atom at the 6-position of the indole.25. The compound of claim 24, wherein the R² at-the 6-position of theindole is Cl.
 26. The compound of claim 20, wherein one R² is C₁₋₆ alkylor halogen atom at the 5-position of the indole and one R² is a halogenatom at the 6-position of the indole.
 27. The compound of claim 26,wherein the R² at the 5-position of the indole is F or Me and the R² atthe 6-position of the indole is Cl.
 28. The compound of claim 20,wherein R³ is C₁₋₆ alkyl.
 29. The compound of claim 28, wherein R² is H.30. The compound of claim 20, wherein R³ is C₁₋₆ alkyl and R² is H orwherein R³ is hydrogen and R² is halogen.
 31. The compound of claim 30,wherein R² is Cl in the 6-position of the indole.
 32. The compound ofclaim 20, selected from the group consisting of:(1-Benzyl-2-methyl-1H-indol-3-yl)-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-methanone;and8-[(6-chloro-1H-indol-3-yl)carbonyl]-1,4-dioxa-8-azaspiro[4.5]decane.33. A pharmaceutical composition comprising a compound of formula I

wherein R¹ is H, C₁₋₆-alkyl, aryl, 5 or 6 membered heteroaryl orsulfonylaryl, each of which is optionally substituted by one or more B,—(CH₂)_(m)—R^(a) wherein R^(a) is: CN, OR^(i), NR^(i)R^(ii), orC₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6membered heteroaryl, each of which is optionally substituted by one ormore B, or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), whereinR^(b) is: C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl,—(CH₂)_(m)—NR^(iii)R^(iv), NR^(i)R^(ii), or C₃₋₆-cycloalkyl, 4 to 7membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl, each ofwhich is optionally substituted by one or more B, or R¹ and R³ togetherwith the indole ring to which they are attached form a 5 or 6 memberedheterocycloalkyl which is optionally substituted by ═O; there is one ormore R², wherein each R² is the same or different, R² is one or more H,OH, halo, CN, nitro, C₁₋₆-alkyl optionally substituted by—NR^(iii)R^(iv), C₁₋₆-alkoxy, —O—CH₂—C₂₋₆-alkenyl, or benzyloxy, or twoR² together with the indole ring to which they are attached form an oxoor dioxo bridge; R³ is H, halo, or —(CO)—R^(c), wherein R^(c) is:C₁₋₆-alkyl, —(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), 5 or 6membered heterocycloalkyl optionally substituted by C₁₋₆-alkyl, orC₁₋₆-alkyl or aryl, each of which is optionally substituted by halo,—O(CO)—C₁₋₆-alkyl, or —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyloptionally substituted by halo or nitro, or R^(d) is aryl or a 5 or 6membered heteroaryl, each of which is optionally substituted by halo,nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl; B is halo, CN, NR^(i)R^(ii),C₁₋₆-alkyl optionally substituted-by CN, halo or C₁₋₆-alkoxy,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)NR^(i)R^(ii), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, —S(O)₂—NR^(i)R^(ii),or (CR^(iii)R^(iv))_(n)-phenyl or (CR^(iii)R^(iv))_(n)-5 or 6 memberedheteroaryl, wherein the phenyl or 5 or 6 membered heteroaryl moiety isoptionally substituted by one or more substituent(s) selected from thegroup consisting of halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionallysubstituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and —S(O)₂—NR^(i)R^(ii); R^(i) andR^(ii) are each independently H, C₁₋₆-alkyl, C₁₋₆-alkyl-NR^(iii)R^(iv),—(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl,—S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv); Riii and R^(iv) are eachindependently H or C₁₋₆-alkyl; m is 1 to 6; n is 0 to 4; and A is eithera group of the formula (a) or (b):

wherein R⁴ is is H or C₁₋₆-alkyl; and R⁵ is aryl optionally substitutedby halo; or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 34. The composition of claim 33,wherein the compound of formula I has formula I-a.
 35. The compositionof claim 33, wherein the compound of formula I has formula I-b.